Investigational growth factors utilized in animal models of spinal fusion: Systematic review

Abstract

BACKGROUND Over 400000 Americans annually undergo spinal fusion surgeries, yet up to 40% of these procedures result in pseudoarthrosis even with iliac crest autograft, the current “gold standard” treatment. Tissue engineering has the potential to solve this problem via the creation of bone grafts involving bone-promoting growth factors ( e.g ., bone morphogenetic protein 2). A broad assessment of experimental growth factors is important to inform future work and clinical potential in this area. To date, however, no study has systematically reviewed the investigational growth factors utilized in preclinical animal models of spinal fusion. AIM To review all published studies assessing investigational growth factors for spinal fusion in animal models and identify promising agents for translation. METHODS We conducted a systematic review of the literature using PubMed, Embase, Cochrane Library, and Web of Science databases with searches run on May 29 th , 2018. The search query was designed to include all non-human, preclinical animal models of spinal fusion reported in the literature without a timespan limit. Extracted data for each model included surgical approach, level of fusion, animal species and breed, animal age and sex, and any other relevant characteristics. The dosages/sizes of all implant materials, spinal fusion rates, and follow-up time points were recorded. The data were analyzed and the results reported in tables and text. PRISMA guidelines were followed for this systematic review. RESULTS Twenty-six articles were included in this study, comprising 14 experimental growth factors: AB204 ( n = 1); angiopoietin 1 ( n = 1); calcitonin ( n = 3); erythropoietin ( n = 1); basic fibroblast growth factor ( n = 1); growth differentiation factor 5 ( n = 4), combined insulin-like growth factor 1 + transforming growth factor beta ( n = 4); insulin ( n = 1); NELL-1 ( n = 5); noggin ( n = 1); P-15 ( n = 1); peptide B2A ( n = 2); and secreted phosphoprotein 24 ( n = 1). The fusion rates of the current gold standard treatment (autologous iliac crest bone graft, ICBG) and the leading clinically used growth factor (BMP-2) ranged widely in the included studies, from 0-100% for ICBG and from 13%-100% for BMP-2. Among the identified growth factors, calcitonin, GDF-5, NELL-1, and P-15 resulted in fusion rates of 100% in some cases. In addition, six growth factors - AB204, angiopoietin 1, GDF-5, insulin, NELL-1, and peptide B2A - resulted in significantly enhanced fusion rates compared to ICBG, BMP...

Pre-Clinical Evaluation of Biological Bone Substitute Materials for Application in Highly Loaded Skeletal Sites

“…This technique aims to fuse two or more vertebrae together in order to treat medical conditions that arise from degenerative, traumatic and oncologic pathologies. However, pseudarthrosis or failed fusion rates are reported to be as high as 40% in primary spinal fusion surgery and up to 60% in revision cases [128], which leads to the need for the improvement of new spinal fusion materials and their evaluation through preclinical models (Table 4). Critical-sized segmental defects are generally defined by considering the diameter of the shaft multiplied by factor 2.0-2.5 [120,121], although some studies report the use of defects three times larger than the diameter of the bone [120].…”

“…This technique aims to fuse two or more vertebrae together in order to treat medical conditions that arise from degenerative, traumatic and oncologic pathologies. However, pseudarthrosis or failed fusion rates are reported to be as high as 40% in primary spinal fusion surgery and up to 60% in revision cases [128], which leads to the need for the improvement of new spinal fusion materials and their evaluation through preclinical models (Table 4). Several studies have shown striking similarities between the spine of humans and quadrupeds, not only in the osseous structural arrangement (suggesting that quadruped and biped spines experience similar loads), but also in mechanical properties of specific spinal segments [133,134].…”

“…This technique aims to fuse two or more vertebrae together in order to treat medical conditions that arise from degenerative, traumatic and oncologic pathologies. However, pseudarthrosis or failed fusion rates are reported to be as high as 40% in primary spinal fusion surgery and up to 60% in revision cases [ 128 ], which leads to the need for the improvement of new spinal fusion materials and their evaluation through preclinical models ( Table 4 ).…”

Oxysterols as promising small molecules for bone tissue engineering: Systematic review

“…To address these issues, extensive work has been performed over the past several decades, creating the field of bone tissue engineering, which comprises all efforts aimed at creating implantable bone substitutes[ 9 ]. In their most basic form, bone tissue engineering products constitute a biological scaffold to facilitate new bone growth often combined with bioactive molecules and/or cells that induce new bone formation[ 9 - 11 ]. One prime example is the Infuse ® Bone Graft (Medtronic Spinal & Biologics; Memphis, TN) – a collagen sponge with adsorbed recombinant human bone morphogenetic protein-2 (rhBMP-2)[ 12 ] that has been used in more than a million neurosurgical and orthopaedic patients since receiving Food and Drug Administration (FDA) approval in 2002[ 12 , 13 ].…”

The effect of electrical stimulation therapies on spinal fusion: a cross-disciplinary systematic review and meta-analysis of the preclinical and clinical data

“…tein-2), 27,43,76 mesenchymal stem cells, 79 novel bone graft substitutes, 31,73 and dynamic instrumentation. 65,91 Postoperative electrical stimulation therapy has also been suggested as an attractive adjuvant therapy to enhance or accelerate bony union.…”